Sun et al. BMC Medical Genetics(2020) 21:215
https://doi.org/10.1186/s12881-020-01146-3

CASE REPORTOpen Access

A novel PIK3R1 mutation of SHORT
syndrome in a Chinese female with diffuse
thyroid disease: a case report and review ofliterature
Liying Sun1†, Qianwen Zhang2†, Qun Li2, Yijun Tang2, Yirou Wang2, Xin Li2, Niu Li3, Jian Wang3 andXiumin Wang2*

Abstract
Background: SHORT syndrome is a rare genetic disease named with the acronyms of short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay. It is inherited in an autosomal
dominant manner confirmed by the identification of heterozygous mutations in PIK3R1. This study hereby presents
a 15-year-old female with intrauterine growth restriction, short stature, teething delay, characteristic facial gestalts
who was identified a novel de novo nonsense mutation in PIK3R1.
Case presentation: The proband was admitted to our department due to irregular menstrual cycle and hirsutism
with short stature, who had a history of intrauterine growth restriction and presented with short stature, teething
delay, characteristic facial gestalts, hirsutism, and thyroid disease. Whole-exome sequencing and Sanger sequencing
revealed c.1960C > T, a novel de novo nonsense mutation, leading to the termination of protein translation (p.
Gln654*).
Conclusions: This is the first case report of SHORT syndrome complicated with thyroid disease in China, identifying
a novel de novo heterozygous nonsense mutation in PIK3R1 gene (p. Gln654*). The phenotypes are mildly different
from other cases previously described in the literature, in which our patient presents with lipoatrophy, facial feature,and first reported thyroid disease. Thyroid disease may be a new clinical symptom of patients with SHORT
syndrome.
Keywords: SHORT syndrome, PIK3R1 gene, Whole-exome sequencing, Novel variant, Case report

Background
SHORT syndrome (MIM 269880; ORPHA:3163) is arare genetic disease whose name is given by Gorlin [1]with the acronyms of short stature (S), hyperextensibilityof joints (H), ocular depression (O), Rieger anomaly (R)* Correspondence: wangxiumin1019@126.com†
Liying Sun and Qianwen Zhang are Co-first author, these authors
contributed equally to the study.
2
Department of Endocrinology and Metabolism, Shanghai Children’s Medical
Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Full list of author information is available at the end of the article

and teething delay (T) [2, 3]. A few cases have been reported in the literature, but the prevalence of SHORT
syndrome remains unclear (< 1:1000000) [4].
The phenotypic presentation most frequently observedin SHORT syndrome are mild intrauterine growth restriction (IUGR), short stature, and a characteristic facial
gestalt (e.g. triangular face with a small thin, thin lip,
downturned mouth, low-set posteriorly rotated ears,
prominent forehead, underdeveloped or thin nasal alae
as well as wrinkles) [3–6]. Lipodystrophy, characterized© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

Sun et al. BMC Medical Genetics(2020) 21:215

by selective loss of adipose tissue, is another typical feature of the syndrome. It is displayed mainly in the face,chest and upper extremities, often sparing the buttocks
and legs [5, 7], causing an aged appearance of the patients suffering from the SHORT syndrome. Insulin resistance is another common characteristic of the disease
while ages at diagnosis is highly variable [4, 8]. Severe insulin resistance may also lead to an early onset of type 2
diabetes, typically occurring in the second decade of life[9]. Additionally, almost all postpubertal women affected
present polycystic ovary syndrome [4, 10]. There aresome other common features of the SHORT syndrome,e.g. ophthalmic abnormalities such as Rieger anomaly,ocular anterior chamber dysgenesis, higher ocular pressure and glaucoma; dental abnormalities such as delayedteething, small teeth and decreased number of teeth;skeletal abnormalities such as delayed bone age, hyperextensibility of the joints as well as clinodactyly [7, 11,12]. Other less common manifestations include delayed
speech development, sensorineural hearing loss, congenital heart defects as well as mild cognitive delay [4,13]. Intelligence is within normal range and most patients can have normal educational achievements [4].
PIK3R1 gene encodes the regulatory subunit of thephosphoinositide 3-kinase (PI3K) holoenzyme, activating
the AKT/mammalian target of rapamycin (mTOR) pathway to modulate cell proliferation and growth [3]. It is
located at 5q13.1 region, containing 16 exons and encoding 724 amino acids. PIK3R1 mutation is associated with two different conditions, that are SHORT
syndrome and a rare primary immunodeficiency disorder named Activated PI3K-delta Syndrome 2(APDS2, MIM615513) [14].
Here, we report a SHORT syndrome case of a 15-year
old female patient in China, exhibiting the classical features of a characteristic facial gestalt, IUGR and delayedteething, though without polycystic ovary syndrome.
The patient also presented diffuse thyroid disease, which
hasn’t been reported in previous studies. Whole exome
sequencing (WES) identified a novel de novo heterozygous mutation(c.1960C > T, p.Gln654*) of the PIK3R1
gene.

Case presentation
The patient was a girl born to a physically healthy andnon-consanguineous couple by spontaneous delivery at
the 37th week. Birth weight was 2150 g (− 3.39SD) andbirth length was 44 cm (− 3.41SD), indicating that thepatient had intrauterine growth restriction (IUGR). The
proband also had teething delay, getting the first tooth
at 1 year old. During childhood, the patient was botheredby short stature. Psychomotor and speech development
was normal. The height of proband’s father and mother

Page 2 of 7

was 168 cm and 155 cm respectively. The patient also
had a healthy 20-month-old brother.
At the age of 15 years and 4 months, the proband wasreferred to our department due to irregular menstrual
cycle and hirsutism with a height of 149 cm (− 2.04SD),
weight of 43 kg (− 1.22SD) and body mass index (BMI)of 19.4 kg/m2. The height of the proband had remained
149 cm, ever since 13 years old. Physical examination
showed a triangular-shaped face, small chin, large lowset ears, thin lip, downturned mouth, obvious beard andbushy eyebrows (Fig. 1a,b,c,d). Oral examination showed
overcrowded and irregular teeth, hypodontia, and severe
dental caries (Fig. 1g). Pubertal development wasassessed according to the Tanner stage, with pubic hairat PH5 stage and breast at B2 stage. The second phalanxof little finger in the left hand was short and thicken,
which was confirmed with X-ray (Fig. 1e,f). Ultrasoundof neck showed diffuse thyroid disease. Ultrasound biomicroscopy of the eyes, examination of ocular fundus,
abdominal ultrasound, reproductive system ultrasound,and chest X-ray were normal. The cranial magnetic resonance imaging (MRI) indicated a small posterior
pituitary.
Laboratory investigations revealed normal levels of routine blood test, liver function, insulin-like growth factor-1(IGF-1, 424 ng/ml), dehydroepiandrosterone sulfate, 17hydroxyprogesterone, cortisol, adrenocorticotropic hormone, β-HCG, follicle-stimulating hormone (FSH),
luteinizing hormone (LH), estradiol, free triiodothyronine(FT3), free thyroxine (FT4), thyroid-stimulating hormone(TSH), triglyceride, cholesterol, and low-density lipoprotein. Abnormal laboratory results of the proband wereshown in Table 1. Oral glucose tolerance test indicatedinsulin resistance while blood glucose was normal(Supplementary Table S1).
WES was performed to make a clear clinical diagnose.
The candidate variants were first screened by a minor allele frequency < 3% against the 1000 Genomes Project,
the NHLBI exome variant server or in 50 HapMap control exomes. Then, short stature, facial abnormalities
were selected as the filtering clinical symptoms toanalyze the screened candidate variants. According to
the guidelines recommended by the American College ofMedical Genetics and Genomics, a pathogenic variant of
PIK3R1 gene was identified to contribute to the patient’s
conditions. Sequencing result indicated c.1960C > T of
PIK3R1 gene a novel nonsense mutation, leading to thetermination of protein translation (p. Gln654*), which
was confirmed by sanger sequencing (Fig. 2). In addition,
direct sequencing results showed the genotypes of proband’s parents were wild-type, suggesting it was a denovo mutation.
The three-dimensional structure of the wild-type(WT) PIK3R1 protein was generated by the SWISS-Sun et al. BMC Medical Genetics(2020) 21:215

Page 3 of 7

Fig. 1 Image of the patient. a, b, c, d. Facial abnormalities included triangular face with a small chin, thin lip, downturned mouth, low-set
posteriorly rotated ears, obvious beard and bushy eyebrows. e, f. Thicken and short second phalanx of little finger in the left hand. g.
Overcrowded and irregular teeth, multiple dental caries

Table 1 Laboratory results of the patient
FactorValue

Reference range

High-density lipoprotein (mmol/L)

0.75

0.90–1.68

Apolipoprotein A1(g/L)

0.93

1.04–2.02

Apolipoprotein B(g/L)

0.4

0.66–1.33

Androstenedione (ng/ml)

5.59

0.10–2.99

Testosterone (nmol/L)

3.23< 1.39IgA(g/L)

3.22

0.67–3.14

Cytotoxic T cell (cells/ul)

1074.02

200–900

B cell (cells/ul)

522.85100–500

Thyroidperoxidase antibodies(TPOAb)(IU/ml)

223.7

0–34

Antithyroglobulin antibodies(TGAb)(IU/ml)

219.6

0–115

MODEL online server and was examined using Pymol
v.1.8.4.0 software (https://www.pymol.org; Schrödinger,
New York, NY, USA). The three-dimensional structureof the mutant PIK3R1 protein was generated by deletingthe amino acid after glutamic acid 654. GMQE (Global
Model Quality Estimation) and QMEAN for the modelare 0.24 and − 1.83, indicating the model is in good quality. The model shows that PIK3R1 G654 is located on
the loop in the C-terminal src-homology 2 (cSH2) domain (Fig. 3). The termination of protein translation
leading to the damage of the cSH2 domain (Fig. 3).

Discussion and conclusion
SHORT syndrome is inherited in an autosomal dominant manner confirmed by the identification of heterozygous mutations in PIK3R1 (phosphoinositide-3-kinase
regulatory subunit 1, MIM 171833) [15], except for twocases that were resulted from the mutation of PRKCE[16] and IGF1R [17] respectively. To date, 12 variantsSun et al. BMC Medical Genetics(2020) 21:215

Page 4 of 7

Fig. 2 Sanger sequencing showed a heterozygous nonsense mutation (c.1960C > T, p.Gln654X in exon 11) in the patient, and the parents werenormal. Black arrows, mutant bases

have been proven to be SHORT syndrome and the missense mutation of c.1945C > T (p. Arg649Trp) was themost common variant [7, 13]. The mutants are distributed
in exons 12, 13, 15, 16, and intron 11 (Supplementary
Fig.S1). Exon 15, encoding the cSH2 domain, covers mostof the mutations (8/12), including all nonsense mutations(p.Lys653*, p.Gln654* (in this study), p.Tyr657*). Apparently, exon 15 is a mutational hot spot.
The proband presented with some common phenotypes such us IUGR (28/32), short stature (33/41), teething delay (26/27), characteristic facial dysmorphim (43/43), and insulin resistant (14/22) (Table 2). However, it
should be noted that some common clinical symptoms
aren’t observed on the patient, e.g., ocular depression(35/37) and lipoatrophy (34/41). As almost all previous
cases are from North America and Europe, natural
physiological differences between races might be the differentiating factor. The clinical manifestations of
SHORT syndrome in patients with PIK3R1 mutation indifferent exons/introns may facilitate the understandingof genotype-phenotype correlations (Table 2). All patients with SHORT syndrome have characteristic facial
gestalts, making it an essential symptom (43/43). Not allfeatures described in the acronyms of SHORT syndrome
are universally seen. A 32 cases meta-analysis showed
only half of the patients have four or more of classic features [3, 4], which is consistent with our findings. Because of lack of cases in different domains, we could notillustrate specific genotype-phenotype correlations. We
also analyzed the phenotypes of cases carrying nonsense
mutations comparing with other cases, it seems that
nonsense mutations have no correlation with severer or
specific phenotypes, probably because the mutations arein the second to last exon, having limited influence on
the protein (Supplementary Table S2).
We describe the dental status of the patient withSHORT syndrome in detail. According to our review,
teething delay is common (26/27) but a detailed

Fig. 3 Homology models of the wild-type PIK3R1 and p.Gln654* mutant PIK3R1. The inter src-homology 2(iSH2) domain and C-terminal srchomology (cSH2) domain are shown in yellow and green respectively, with the PIK3R1 G654 shown in red

Sun et al. BMC Medical Genetics(2020) 21:215

Page 5 of 7

Table 2 Clinical Features of the patient and reported SHORT patients with Mutations in PIK3R1

Mutation site

The
proband

Domainna

iSH2

Exon 15

Intron 11

Exon 12cSH2
Exon 13na

Exon 15

Exon 16

Total

Number of cases

1

3

1

1

36

2

43

Sex

F

F1/M2

F

M

F21/M15

M2

F23/M20

Premature birth

–

0/2

1/1

1/1

5/22

nd

7/26

IUGR

+

nd

1/1

1/1

26/28

0/2

28/32

Weight at birth <3rd per

+

2/2

1/1

1/1

25/27

0/2

29/33

OFC at birth <3rd per

nd

0/1

1/1

1/1

9/13

nd

11/16

+

1/3

1/1

1/1

30/34

0/2

33/41

SHORT acronym signs
Short stature
Hyperextensibility of joints

–

1/2

0/1

0/1

7/25

0/2

8/31

Ocular depression

–

1/1

1/1

1/1

30/32

2/2

35/37

Rieger anomaly

–

nd

0/1

0/1

14/33

2/2

16/37

Teething delay

+

2/2

1/1

1/1

21/22

1/1

26/27

Characteristic facial dysmorphim

+

3/3

1/1

1/1

36/36

2/2

43/43

Progeroid appearance

+

2/2

nd

nd

14/14

nd

16/16

Lipoatrophy

–

2/2

1/1

1/1

30/35

0/2

34/41

Thin, wrinkled skin with readily visible veins

nd

1/1

1/1

1/1

15/20

0/2

18/25

Other signs

Ophthalmological abnormalities
Glaucoma

–

nd

nd

nd

3/13

nd

3/13

Hyperopia

–

nd

1/1

1/1

5/10

0/2

7/14

Astigmatism

–

nd

0/1

1/1

4/12

nd

5/14

Myopia

+

nd

0/1

0/1

5/13

nd

5/15

Overcrowded teeth

+

1/1

nd

nd

4/5

nd

5/6

Delayed bone age

–

nd

1/1

1/1

4/8

nd

6/10

Inguinal hernia

nd

nd

0/1

0/1

3/19

nd

3/21

Intellectual deficiency

–

1/3

nd

nd

2/17

0/2

3/22

Speech delay

–

1/1

1/1

1/1

10/18

1/2

14/23

Diabetes

–

nd

0/1

0/1

10/21

nd

10/23

Insulin resistance

+

nd

1/1

1/1

11/20

nd

14/22

Hearing loss

–

3/3

nd

nd

5/13

1/2

9/18

Frequent infections

–

3/3

0/1

0/1

3/8

nd

6/13

Congenital heart diseasesb

–

2/2

nd

nd

1/2

nd

3/4

Pulmonary stenosisc

–

1/1

nd

nd

3/4

nd

4/5

Ovarian cystsd

–

nd

nd

na

8/9

na

8/9

a

IUGR intrauterine growth restriction; occipitofrontal circumference; SHORT short stature (S), hyperextensibility of joints (H), ocular depression (O), Rieger
abnormality (R) and teething delay (T); na not applicable; and nd no dataaFrequent infections include respiratory infection, pneumonia, and urinary infectionbCongenital heart diseases include mitral dysplasia, and ventricular septal defectcThis contains a case of pulmonary hypertensiondThis contains a case of Ovarian cancer

observation of dental status is often ignored by researchers. Usually, inherence plays an important role inteeth development. Thus, dental problems like overcrowded teeth (5/6), hypodontia, and dental caries in

SHORT syndrome patients warrant a closer look and early
identification before they progress further down the road.
Diffuse thyroid disease with positive TPOAb and
TGAb has not been reported before in patients with

Sun et al. BMC Medical Genetics(2020) 21:215

SHORT syndrome [4]. PIK3R1 RNA is expressed moderately in the thyroid and it regulates PI3K–AKT signaling
pathway [3]. Evidence shows that PI3K–AKT signaling
pathway is important in the progression of thyroid cancer, it is touted to be a target of a possible treatment forpatients with advanced types of thyroid carcinoma [18].
On the other hand, the relationship between insulin resistance and thyroid function have been controversial[19]. Positive TPOAb and TGAb do exist in the general
population. In this patient, we could not make surewhether it is induced by the mutation directly or not. So
far, the patient’s thyroid function seems to be normal.
Still, a future follow-up is needed as thyroid disease may
be a new clinical symptom of patients with SHORT syndrome and more evidence is necessary to support thishypothesis.
As mentioned above, APDS2 can be triggered by
PIK3R1 mutations. So, it is important to distinguish
APDS2 from SHORT syndrome. Features of APDS2 arerecurrent upper tract respiratory infections and lymphoproliferation. Immunological evaluation of the patient
may show elevated IgM, IgA deficiency, low CD4 andCD8 naïve T cell counts, and B-cell lymphopenia. It
should be noted that 3 cases have been reported withdiagnosis of SHORT syndrome and APDS2 synchronously [14, 20]. The 3 cases are all splicing variants,
resulting in the skipping of exon 11 [14]. Exon 11 encodes the inter-SH2 domain of the p85α isoform, associating to the p110δ catalytic subunit binding [21]. All of
the studies above have different findings compare tothat of our patient’s mildly abnormal level of immune
cells and elevated IgA level. Besides, our patient did
not have a history of recurrent infection, which indicates there was no serious problem with her immune
system. Thus, the diagnosis of APDS2 can be excluded from our patient. It is generally recommended
that APDS2 patients be assessed by a clinical geneticist to exclude concurrence with SHORT syndrome.
Conversely, patients with SHORT syndrome shouldhave their immune system assessed, especially when
they have a history of recurrent respiratory infections
and/or lymphoproliferation [14].
Polycystic ovary syndrome (PCOS) develops almost in
all postpubertal women (8/9) with SHORT syndrome[4], whose features include irregular menstrual cycle,
hirsutism, acne, hyperandrogenemia, and insulin resistance. Elevated androstenedione and testosterone level
could explain the hirsutism and irregular menstrual
cycle of our patient. However, normal reproductive system ultrasound did not support the diagnosis of PCOS.
Still, considering the more stringent diagnostic criteria
for PCOS in adolescence compared to that of adults,
there is a considerable chance for our patient to be diagnosed with PCOS later in her adult life.

Page 6 of 7

In conclusion, our study reported on a Chinese patientwith SHORT syndrome, identifying a novel de novo heterozygous nonsense mutation in the PIK3R1 gene (p.
Gln654*). The phenotypes of the proband were mildly
different from other cases previously reported. Common
clinical symptoms like ocular depression and lipoatrophy
weren’t observed on the patient while diffuse thyroid disease was presented. We aimed to expand the spectrumof genotypes and phenotypes of SHORT syndrome
through this case report. Nevertheless, the precise
genotype-phenotype correlations and molecular mechanisms of SHORT syndrome remain elusive and further
study is warranted.

Supplementary information
Supplementary information accompanies this paper at https://doi.org/10.
1186/s12881-020-01146-3.
Additional file 1: Table S1. Oral glucose tolerance test of the patient.
Additional file 2: Table S2. Clinical Features of the patients with
nonsense mutations in PIK3R1.
Additional file 3: Figure S1. The schematic diagram of the distributionof 12 reported mutations as well as p.Gln654* in PIK3R1 gene.
Abbreviations
IUGR: Intrauterine growth restriction; PI3K: Phosphoinositide 3-kinase;
WES: Whole exome sequencing; MRI: Magnetic resonance imaging;
PCOS: Polycystic ovary syndrome
Acknowledgements
The authors thank the family for participating and supporting this study.
Authors’ contributions
X. W designed the study; L. S and Q. Z drafted and revised the manuscript;
Q. Z, Q. L, Y. T, Y. W, X. L, N. L, and J. W acquired, analyzed, and interpreted
the data. All authors read and approved the final manuscript.
Funding
This work was supported by Pudong New Area Science and Technology
Development Fund (Grant PKJ2018-Y46). The funder supported the clinicalexamination, lab analysis and paper writing.
Availability of data and materials
The raw datasets generated and/or analysed during the current study are
not publicly available in order to protect participant confidentiality. The data
and materials are available from the corresponding author upon reasonable
request.
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Shanghai Children’s
Medical Center (SCMCIRB-Y2019049), Shanghai Jiao Tong University Schoolof Medicine. Written informed consent to participate was obtained from thepatient’s parents.
Consent for publication
Written informed consent for publication of identifying images and otherpersonal or clinical details was obtained from the patient’s parents. And the
copy of the written consent is available for review by the editor of thisjournal.
Competing interests
The authors declare no conflict of interest.

Sun et al. BMC Medical Genetics(2020) 21:215

Author details
1
Department of Pediatric and Adolescent Gynecology, The Children’s
Hospital of Zhejiang University School of Medicine, National Clinical ResearchCenter for Child Health, Hangzhou, China. 2Department of Endocrinology
and Metabolism, Shanghai Children’s Medical Center, Shanghai Jiao Tong
University School of Medicine, Shanghai, China. 3Department of Medical
Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical
Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Received: 12 July 2020 Accepted: 12 October 2020

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